This project is aimed at exploring the underlying biochemical mechanisms of two animal models for the human Fanconi syndrome. The first model is one produced in rat renal tubule by use of succinylacetone which is found in the urine of infants with hereditary tyrosinemia and the Fanconi syndrome; the second model is produced by use of maleic acid, the cis-isomer of fumaric acid. In the course of normal human tyrosine catabolism a unique compound, maleylacetoacetate, is produced; thus a potential explanation for the human renal tubular disorder involves intracellular cleavage of maleylacetoacetate, release of free maleate within the tubular epithelium and production of tubular dysfunction in a fashion similar to that of the animal model. In order to explore this possibility, the following are proposed: a. to characterize fully the in vitro effects of succinylacetone on membrane transport of sugars and amino acids, using both the isolated rat renal tubule and brushborder membrane vesicle preparations. b. to determine the intracellular effects of succinylacetone and maleate on renal tubular heme biosynthesis and incorporation by monitoring Alpha-aminolevulinic acid dehydratase activity, 14C-succinate incorporation into Alpha-aminolevulinate, cytochrome P450 content and 02 consumption. c. to determine in the newborn and developing rat renal tubule the membrane transpost and heme biosynthetic effects of succinylacetone as in (a) and (b), and to compare these effects to those of maleate. d. to determine the role of renal cortex in conversion of maleylacetoacetate to maleate by enzymatic hydrolysis during production of succinylacetone from tyrosine in cytosolic preparations.